GB2249548A - Amines - Google Patents

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GB2249548A
GB2249548A GB9125683A GB9125683A GB2249548A GB 2249548 A GB2249548 A GB 2249548A GB 9125683 A GB9125683 A GB 9125683A GB 9125683 A GB9125683 A GB 9125683A GB 2249548 A GB2249548 A GB 2249548A
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compound
formula
acid
give
bis
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Michael Christopher Wa Minchin
John Frederick White
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton

Abstract

Compounds of formula Ib <IMAGE> and salts thereof, wherein E is lower alkyl or Ar<1>-A<1>; Ar and AR<1> are the same or different optionally substituted aryl groups; A and A<1> are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar<1> to N, each optionally substituted by lower alkyl or optionally substituted aryl; B is an alkylene group of 3 or 4 carbon atoms which may be substituted by lower alkyl; D represents CN, COhal, CH2OH, CHO or an ester function COOR providing that (i) neither Ar-A or E is unsubstituted benzyl, and (ii) when B is -(CH2)4 and D is CN then E is other than methyl, ethyl or p-chlorobenzyl, are intermediates in the preparation of pharmaceutically active amines.

Description

AMINES This invention relates to use of a new pharmacological activity and to certain amines possessing said pharmacological activity, to processes for preparing them and to pharmaceutical compositions containing them. More particularly this invention relates to the treatment of depression.
In the UK the annual referral rate for depression is around 300-400 per 105 population of whom 10-15% require hospitalisation. At present the most effective and safe treatment for severe depression involves electroconvulsive therapy (ECT) where the patient receives a series of controlled electric shocks.
However such treatment understandably engenders an atavistic fear and apprehension in many patients. It also has undesirable side-effects, notably disturbance of memory.
ECT is also expensive and time-consuming to administer, requiring the presence of specialist doctors such as psychiatrists and anaesthetists. As an alternative to ECT, drug therapy provides a more acceptable treatment for the patient but at the present time such therapy has not displaced ECT as the optimal treatment in severe cases because it is not always effective. There is therefore a need for new drugs for the treatment of depression, especially drugs having new modes of action mimicking ECT.
The mode of action of ECT remains unknown but in recent years much has been learnt about the biological effects of electroconvulsive shock (ECS) in animals. In particular, repeated ECS, given in ways closely mimicking those used to administer ECT clinically, elicits in rodents changes in monoamine functions. These include: increased 5-HT-mediated behaviour, increased dopaminergic behaviour and depressed beta-adrenoceptor binding and sensitivity of the coupled adenylate cyclase. The last is also seen following chronic treatment with a number of antidepressant drugs.
The effects of repeated ECS are presumably a response or adaptation to the acute effects of the seizures.
Among these acute effects are a marked change in the release, synthesis and level of gamma aminobutyric acid (GABA) in the brain. - see Green A.R. et al, British J.
Pharmacol., 92, 5-11 and 13-18 (1987) and Bowdler et al; ibid, 76, 291-298 (1982).
GABA is one of the most widespread and abundant transmitters in the mammalian central nervous system and plays a major role in the control of brain excitability. It is similarly implicated in the benzodiazepine-mediated relief of anxiety. Recently, evidence has come to light which suggests that GABA transmission may also be involved in the therapeutic effects of some antidepressant treatments. In particular, new compounds designed as GABA agonists (eg. fengabine and progabide) have been shown in preliminary clinical trials to have antidepressant activity (vide infra). Taken together, these findings suggest that interventions directed specifically at GABA transmission may provide the basis of novel therapies for the treatment of affective disorders.
At present three GABA receptors have been identified in the central nervous system. These are (1) a GABAA receptor known to be mainly postsynaptic and mediating inhibition of neuronal firing - see for example Stephenson, F.A. Biochem, J., 249 pp 21-32 (1988); (2) a GABAB receptor located presynaptically and mediating the inhibition of release of a number of neuro-transmitters, eg. noradrenaline and aspartic acid, but not GABA - see for example Bowery, N.G. et al, Nature, 283, 92-94 (1980); and (3) a GABA autoreceptor which modulates the release of GABA from neurones - see for example Mitchell, P.R., and Martin, I.L. Nature, 274 904-905 (1978); Arbilla, S. Kanal, J.L and Langer, S.Z. Eur.J.Pharmac., 57, 211-217 (1979) and Brennan M.J.W. et al, Molec.
Pharmac., 19, 27-30 (1981).
The pharmacological importance of these receptors is currently a subject of investigation with a major part of the work involving the search for anticonvulsant drugs with a mode of action involving GABAA receptors.
Two drugs acting on GABA receptors, progabide and fengabine, have also been shown to possess antidepressant effects in preliminary clinical trials see P.L. Morselli et al, L.E.R.S. Vol 4 (1986) pp 119-126 and B.Scatton et al, Journal of Pharm. and Exp.
Therapeutics., 241, 251-257 (1987). The latter workers showed that fengabine possessed a biochemical mode of action different from that of conventional antidepressants but that the mechanism whereby fengabine exerted its antidepressant actions was not yet clear. It was thought to derive from a GABAergic action, most likely at GABAA receptors.
In the case of progabide, Morselli et al also attributed the antidepressant effect to an increased GABAergic transmission.
We provide evidence herein that the antidepressant effect of progabide and fengabine is in fact due to their agonist action at the GABA autoreceptor.
The GABA autoreceptor is capable of regulating the release of GABA from GABAergic neurons which means an agonist at the autoreceptor would decrease the GABA release hence decreasing GABA function ie. an action opposite to that of GABAA agonists.
As far as we are aware it has not been suggested even remotely that the GABA autoreceptor is linked to an antidepressant effect. Previously the autoreceptor was believed to have the same pharmacology as the GABAA site - see Molec. Pharm, 19,27-30 (1981).
We have now surprisingly found that the GABA autoreceptor has its own distinct pharmacology and that there are compounds having selective agonist activity at the GABA autoreceptor. These compounds have valuable medical uses.
Accordingly in one aspect this invention provides a compound for use in treating depression characterised in that the compound has selective agonist activity at GABA autoreceptors and a pharmaceutical composition comprising such a compound.
This invention also provides a method for treating depression in humans which comprises administering an effective amount of a compound which possesses selective agonist activity at GABA autoreceptors.
This invention also provides a pharmaceutical composition for treating depression which comprises a compound possessing selective GABA autoreceptor agonist activity and a pharmaceutical acceptable carrier.
There is evidence that compounds acting at the benzodiazepine receptor as inverse agonists decrease GABA function in the brain and thus increase acetylcholine transmission. In addition, probably as a consequence of these actions, they facilitate memory in animals and man (see Sarter. M. et al. Trends in Neuroscience, 11 13-17, 1988). Compounds acting selectively as GABA autoreceptor agonists would be expected to have similar actions.
Accordingly, another aspect of this invention provides a compound having selective agonist activity at GABA autoreceptors for use in the preparation of a medicament for treating senile dementia and other forms of memory impairment. This invention also provides a method of treating senile dementia and other forms of memory impairment in mammals which comprises administering an effective amount of a compound which possesses selective agonist activity at GABA autoreceptors.
In this invention it is preferred that the compound having GABA autoreceptor agonist activity is selective in that it has little or no activity at GABAA receptors. This is because GABAA agonist activity would tend to counteract the effect of the autoreceptor agonist. GABAA antagonist activity tends to cause convulsions. For example the selectivity for the GABA autoreceptor relative to the GABAA receptor is preferably greater than 100, most preferably greater than 1000.
We have found that one general class of compounds in which selective GABA autoreceptor agonist activity can be observed is tri-substituted amines in which one of the substituents is a 3- or 4-alkanoic acid which itself may be substituted and derivatives thereof, such as an amide or substituted amide. Within such a general class the observation of GABA autoreceptor activity depends on the nature of the substituents.
In a further aspect of this invention there are provided compounds having a tri-substituted amine structure with one substituent being a 3- or 4- carbon alkyl group carrying a carboxylic acid or amide function possessing selective GABA autoreceptor agonist activity. More particularly this invention relates to mono- and di-(arylalkyl)amine derivatives and related compounds possessing pharmacological activity, and intermediates of closely related structure.
Certain di-(arylalkyl)amine derivatives are known in the literature. The reaction of dibenzylamine with 3-chloropropyl cyanide to give 3-dibenzylaminopropyl cyanide and subsequent hydrolysis of the cyanide to give 4-dibenzylaminobutyric acid hydrochloride is described by M E Gittos and W Wilson in Journal of the Chemical Society,(1955) 2371-2376. The latter compound is also described in Chemical Abstracts 106, 78248(1987) where it is used to prepare derivatives of daunorubicin. 4-Dibenzylaminobutyramide and 4-dibenzylaminopropyl cyanide are disclosed in Chemical Abstracts 97, 163499m as intermediates in the preparation of 4-aminobutyric acid amide hydrochloride.
Various -dibenzylaminoalkyl cyanides and related compounds are disclosed in J. Med. Chem., 1975 18(3) 278-284 as starting materials for fibrin stabilizing factor inhibitors.
Accordingly this invention provides a compound for use as a pharmaceutical having formula:
or a salt thereof,wherein E represents lower alkyl or a group Ar -A1-; Ar are the same or different aryl groups (including heteroaryl) which are optionally substituted, eg. by one or more substituents commonly used in pharmaceutical chemistry such as lower alkyl, lower alkoxy, halogen, haloloweralkyl, haloloweralkoxy, cyano, amino (including substituted amino eg. mono- or di-loweralkyl amino) and nitro; A and A are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar to N and optionally substituted by lower alkyl and/or optionally substituted aryl, B is an alkylene group of 3 or 4 carbon atoms1 which may be substituted by lower alkyl;; D1 12 1 2 represents CONR R2 or COOH where R and R are independently hydrogen1 lower alkyl or aralkyl of 7 to 12 carbon atoms.
The compounds of formula Ia can be prepared from intermediates of formula Ib
wherein Ar, A, E and B are as defined above and D represents CN, COhal, CH2OH, CHO or an ester function COOR.
By the term lower is meant a group containing 1 to 6 carbon atoms.
Examples of Ar and Ar1 are mono- or bi-cyclic aryl groups such as carbocyclic aryl groups of 6 to 1 carbon atoms (eg. phenyl or naphthyl) and heteroaryl groups of 5 to 10 ring atoms in which the heteroatom is selected from oxygen, nitrogen and sulphur (eg.
pyridine, furan, thiophene) or aromatic groups containing two or more such heteroatoms (eg.
thiazolyl). Bicyclic heteroaryl groups are exemplified by quinoline and benzofuran.
Examples of A and A are independently -(CH2)m optionally substituted by lower alkyl and/or aryl where m is 1 or 2. Preferably A and A are independently 3 3 -CHR - where R is hydrogen, lower alkyl, eg. methyl or ethyl, or optionally substituted aryl as defined for Ar, eg. phenyl. Examples of B are -CH2CH2CH2- and -CH2CH2CH2CH2- which groups may be substituted by lower alkyl such as methyl, eg. B represents -CH(CH3)CH2CH2 or -CH2CH(CH3)CH2-.
Examples of R1 and/or R2 are hydrogen, methyl, ethyl, propyl and benzyl.
Some compounds of formula Ib are known compounds.
Accordingly in a further aspect this invention provides a compound of formula I (including compounds of formula Ia).
wherein E, Ar, Ar, A, A and B are as defined above and D is COOH or CONRR wherein R and R are as defined above or D is CN, COhal, CH2OH, CHO or COOR where COOR represents an ester function (eg. R = optionally substituted alkyl, aitalkyl or aryl) providing that (i) neither Ar-A or E is unsubstituted benzyl and (ii) when B is -(CH2)4- and D is CN then E is other than methyl, ethyl or p-chlorobenzyl.
Compounds of formula I wherein D is CN, COhal, CH2OH, CHO or COOR where R is as defined above are useful as intermediates to compounds of formula I wherein D is COOH or CONR R 4 The compounds of formula Ia as defined above possess pharmacological activity especially activity affecting the nervous system. In particular the compounds of formula Ia are inhibitors of gamma aminobutyric acid (GABA) release from nerve terminals via action on the GABA autoreceptor.
A number of compounds have previously been shown to be agonists at the GABA autoreceptor, for example muscimol, isoguvacine and THIP (see Merck Index 1983 No. 9214) but such compounds are non-selective in that they are also active at other GABA receptors (ie. GABAA and /or GABAB). As far as we are aware no medical use has been attributed to the above-mentioned compounds based on their GABA autoreceptor activity.
Compounds showing selective properties at the GABA autoreceptor are desirable since additional activity at the other GABA receptors would cause many side effects such as sedation and adverse muscle tone actions.
The compounds of formula Ia demonstrate activity at GABA autoreceptors, more specifically they demonstrate agonist activity as shown by standard in vitro test procedures. Advantageously compounds of formula Ia appear to be selective in that they display little or no activity at GABAA or GABAB receptors. The following test procedures were used to measure activity at (a) GABA autoreceptors and GABAB receptors by inhibition of potassium-evoked GABA and noradrenalin release from rat cortex in vitro (Procedure 1); and (b) GABAA receptors by enhancement of [3H]-flunitrazepam binding in rat cortex in vitro (Procedure 2): Procedure (1) Slices (0.25 x 0.25 x 2.0 mm) of rat cerebral cortex are prepared using a McIlwain tissue chopper. The slices are incubated in Krebs-Henseleit solution cotaining [ H]-GABA (10-7M) and [14C]-noradrenaline (107M) in the presence of amino-oxyacetic acid (AOAA) (10 5M), pargyline (106M) and ascorbic acid (10.4M), for 20 minutes at 37"C, rinsed with 5 ml aliquots of Krebs-Henseleit solution and transferred to 10 superfusion chambers (volume 300ul). The slices are continuously superfused with Krebs-Henseleit solution (0.4 ml min ) containing AOAA (10 and fractions of the superfusate collected every 4 minutes. Transmitter release is induced by 4 minute exposure to a Krebs-Henseleit solution containing 25 mM potassium (with concomitant reduction in sodium to maintain osmolarity) after 68 (S1) and 92 (S2) minutes of superfusion.The compound under study is added to the superfusing medium 20 minutes prior to the second potassium stimulation. The residual radioactivity in the slices at the end of the experiment together with that in the superfusate fractions is measured by liquid scintillation counting using a dual label programme for tritium and carbon14, Calculations: The amount of radioactivity (either tritium or carbon-14) in each fraction is expressed as a percentage of the respective total radioactivity in the tissue at the start of the respective collection period. The amount of radioactivity released above basal by the increased potassium is calculated and the ratio S2/S1 obtained. The S2/S1 ratio from drug-treated slices is expressed as a percentage of the control S2/S1 ratio.For compounds achieving inhibition of 30% or more pD2 values are calculated from plots of inhibition of release versus concentration of drug. Failure to inhibit the release of noradrenaline indicates that the molecule has no GABAB agonist activity.
Procedure (2) Cortices from six or more rats are excised and homogenised in 50 volumes (volume/weight) 50mM Tris buffer (pH 7.4 at 37"C) using a Polytron homogeniser on speed 5 for 30 seconds. Tissue is kept at OOC throughout the procedure. The homogenate is centrifuged at 40,000 x g for 15 minutes and the pellet resuspended (Polytron 5, 10 sec.) in 50 volumes (original weight) of Tris buffer. Centrifugation and resuspension is repeated followed by incubation at 37"C for 10 minutes. The homogenate is centrifuged (40,000 x g, 15 min), resuspended in 10 volumes (original weight) Tris and stored below -20 C for more than 24 hours.
On the day of the experiment, membranes are thawed at 37"C and made up to 20 volumes (original weight) with Tris Krebs (20mM, see below). The membranes are homogenised (Polytron 5, 30 sec), incubated at 37"C for 15 minutes and centrifuged at 20,000 x g for 10 minutes. This wash and resuspension is repeated two more times with the final pellet resuspended in 100 volumes (original weight) Tris Krebs ready for use.
The test compound (50ul) and 20nM (final concentration) [3H-flunitrazepam (SOul) are dispensed in triplicate.
The reaction is started by the addition of 900ul of membrane preparation. After a 30 minute incubation at 37"C the reaction is stopped by filtration through Whatman GF/B filters under reduced pressure using a Brandell Cell Harvester, with two 7.5 ml filter washings. The radioactivity retained on the filters is measured by liquid scintillation counting.
Tris Krebs composition: NaCl-136mM, KCl-5mM, MgSO4-2mM, KH2PO4-2mM, CaCl2-2mM, Tris buffer (pH 7.4 at 37 C)-20mM, ascorbic acid-lmM, disodium ethylenediamine tetraacetic acid-lmM.
Calculations: Results are calculated as follows: dpm sample (enhanced binding) x 100 = % control dpm control (non-enhanced binding) RESULTS In the aforementioned tests the following representative compounds gave the results shown: Compound GABA Inhibition Enhance autoreceptor of release ment of pD2 values of noradren- [3H]-flu aline at nitrazepam 10-5M binding 4-[N,N-Bis-(4- 7.0 0 0 -Chlorobenzyl)amino]butyric acid 4-[N,N-Bis-(4- 6.6 0 0 Chlorobenzyl)amino ]butyramide 4-(N,N-Dibenzy- 7.0 > 20% 0 lamino)butyramide 4-(N,N-Dibenzy- 7.1 20% 0 lamino)butyric acid 4-[N,N-Bis-(4- 7.4 10% 0 Methylbenzyl)amino]butyric acid 4-[N,N-Bis-(3,4- 7.5 0 0 dichlorobenzylamino]butyric acid 4-[N,N-Bis-(4- 6.0 0 0 methoxybenzyl) amino]butyramide 4-[N-(p-chloro- 7.5 0 0 benzyl)-N-methyl] aminobutyramide In the aforementioned tests fengabine was found to have a PD2 value of 8.0 at the GABA autoreceptor and little or no activity at GABAA and GABAB sites in vitro. We attribute the antidepressant activity observed for fengabine to its potent selective GABA autoreceptor activity. Progabide was also active at the GABA autoreceptor. We make no claim to the use of fengabine or progabide in the preparation of a medicament for use as an antidepressant.
The compounds were also tested for their effect on a GABA synapse in vivo in the following procedure: Procedure 3 Experiments were performed on male albino rats (240-280g) lightly anaesthetized with urethane (1.2-1.4 g/kg i.p.) or Halothane (0.7-1.0% in 2) The animal's temperature was maintained between 36-38"C via a thermostatically controlled heating blanket.
The caudate nucleus and substantia nigra were approached dorsally after exposing the overlying cortex. Pulsations of the brain and cerebral oedema were minimised by allowing cerebral spinal fluid to leak from a cisternal puncture. The exposed cortex was bathed in warm liquid paraffin throughout the experiment. A coaxial bipolar stimulating electrode (tip separation 0.25mm) was positioned stereotaxically in the caudate nucleus such that the tip of the electrode corresponded to the area delineated by the co-ordinates L 2.5; A 8.5-95; D 5. (Paxinos and Watson. 1986). Square wave pulses (50-300pA 0.1-0.2msec duration) were delivered at 0.5-1.OHz via the stimulating electrode to evoke inhibitory, GABA-mediated synaptic responses in nigral neurones.
Extracellular recordings were obtained from single neurones in the ipsilateral substantia nigra via either the centre barrel (3.5M Nail) of a multibarrelled microelectrode or a single barrelled electrode (3.5M Nail), attached to but protruding 10-20 ij beyond, a multibarrelled electrode. The electrodes were lowered into the substantia nigra via a remote controlled stepping micromanipulator such that the electrode tip corresponded to the stereotaxic co-ordinates L1.5-2.5; A 3.0-4.0; D 7.0-8.5 (Paxinos and Watson, 1986). Unit firing was amplified, continuously monitored on an oscilloscope, electronically counted and displayed by a chart recorder and fed into a computor for the generation of peristimulus time histogrames (PSTH) of synaptic responses.Each outer barrel of the multibarrelled electrode was filled with aqueous solutions of the following which were administered in the vicinity of the recorded neurones using standard microiontophoretic techniques: Compound of Example 5 (0.1M or 0.01M in 0.9% NaCl, pH 5.5), GABA (0.2M, pH 3.5), glycine (0.2M, pH3.5), dl-homocysteate (DLH) (0.2M, pH 7.2), N-methyl-D-Aspartate (NMDA) (0.05M in 0.165M NaCl, pH 7.0), quisqualate (0.02M in 0.165M NaCl, pH7.0), kainate (0.2M in 0.165M NaCl, pH 7.0) and bicuculline methochloride (BMC) (0.005M in 0.165M NaCl, pH 5.0). Effects of agonist drugs on the GABA autoreceptor could be measured as an attenuation of the synaptic inhibition evoked by stimulation of the caudate. GABAA receptor agonism could be tested by ejecting drug directly onto the nigral meurone in the absence of synaptic inhibition.
The location of the recording and stimulating electrodes in the brain were verified after each experiment by histological examination.
Reference Paxinos G & Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press.
Result In this test the compound of Example 5 almost abolished synaptically-evoked, GABA-mediated inhibition in the substantia nigra without affecting postsynaptic GABAA receptors, when it was ejected iontophoretically in the vicinity of nigral neurones. This action of the compound of Example 5 was reversible and is entirely consistent with a selective agonist action at the GABA autoreceptor In another aspect this invention provides a compound of formula Ia for use as a pharmaceutical.
This invention also provides processes for preparing the compounds of the invention, including processes for preparing the pharmacologically active compounds of formula Ia via intermediates of formula I wherein D is CN, COOR, CHO, CH2OH or COhal.
Compounds of formula I may be prepared by any one of the following processes: a) reacting a compound of formula II Ar-A-NH-E (II) wherein Ar, E and A are as defined above with a compound of formula III: hal-B-CN (III) wherein B is as defined above and hal represents chlorine or bromine1 to give a compound of formula I wherein D is CN, or b) carrying out a reductive alkylation of a compound of formula II as defined above using a compound of formula IV
wherein B1 is an alkylene chain of 2 or 3 carbon atoms optionally substituted by lower alkyl, in the presence of a reducing agent such as sodium cyanoborohydride to give a corresponding compound of formula I wherein D is CN and B represents -CH2-B -; or (c) reducing a compound of formula (V)
wherein R4 is alkyl of 1 to 5 carbon atoms or Ar -A2-; Ar, Ar, A and B are as defined above1 D represents CN, COOR or COOH and A represents a direct bond or alkylene of 1 carbon atom optionally substituted by lower alkyl and/or aryl to give a corresponding compound of formula I wherein D is CN, COOR or COOH and E is R4CH2 wherein R is as defined above; or (d) reducing a compound of formula (VI)
wherein Ar, A and E are as defined above, B1 is as defined in connection with formula IV and D2 represents CN, COOR or CHO to give a corresponding compound of formula I wherein B is -CH2B- and D is CN, COOR or CHO, or (e) partially hydrolysing a compound of formula I wherein D is CN to give a corresponding compound of formula I wherein D is CONH2; or (f) hydrolysing a compound of formula I wherein D is CN or CONH2 to give a corresponding compound of formula I wherein D is COOH; or (g) reacting a compound of formula I wherein D is COOR or COhal with ammonia or an amine of formula HNR R to give a corresponding compound of formula I wherein D is -CONR R ; or (h) hydrolysing an ester of formula I wherein D is COOR to give a carboxylic acid of formula I wherein D is COOH; or (i) oxidising an aldehyde of formula I wherein D is CHO to give an acid of formula I wherein D is COOH; or (j) oxidising an alcohol of formula I wherein D is -CH2OH to give an aldehyde or an acid of formula I wherein D is CHO or COOH; or (k) oxidising a compound of formula
wherein Ar, A, E and B are as defined above and D3 is COCH3,-C#CH or-CH=CH2 to give a compound of formula I wherein D is COOH; or (l) hydrolysing a compound of formula
1 2 wherein Ar, A and E are as defined above,T and T are each independently an ester function2 a nitrile or an 1.
acyl group, and B is an alkylene group of 2 or 3 carbon atoms optionally substituted by lower alkyl to give a corresponding compound of formula I wherein B is -B -CH2 CHO and D is COOH; or (m) esterifying an acid or acid halide of formula I wherein D is -COOH or COhal to give an ester of formula I wherein D is-COOR; or (n) halogenating an acid of formula I to give an acid halide of formula I wherein D is COhal; or (o) reducing an acid of formula I wherein D is COOH to give an alcohol of formula I wherein D is CH2OH, or (p) acidifying a compound of formula I to give an acid addition salt thereof or neutralising an acid addition salt to give the free base form.
With regard to process (a) the reaction may be conveniently carried out in the presence of an inert solvent and a base such as a tertiary amine (erg.
diisopropylethylamine) with heating if required.
Examples of suitable inert solvents are dimethylformamide, acetonitrile and dimethylsulphoxide.
With regard to process (b) the reductive alkylation is conveniently carried out in an inert solvent, depending on the reducing agent, and without heating. When the reducing agent is sodium cyanoborohydride the solvent may be an aqueous alcohol such as aqueous ethanol.
Catalytic hydrogenation may also be used, eg using Pd/C and an alcohol solvent, eg. ethanol.
Process (c) and (d) may both be carried out using a suitable reducing agent not affecting the D or D group for example ionic hydrogenation see Kursanor et al, Synthesis 1974, Vol 9, 633-651. Other reducing 2Dents may be used, eg. diborane or Raney nickel.
With regard to process (e) the partial hydrolysis of the nitrile to give the amide may be carried out in conventional manner under acidic or basic conditions.
Methods for carrying out the transformation are extensively described in the literature - see for example the textbook Buehler and Pearson Survey of Organic Syntheses, Wiley Interscience, 1970 pages 903-904, and references cited therein. The preferred method is to carry out the hydrolysis using aqueous sodium hydroxide in the presence of hydrogen peroxide and a phase transfer catalyst.
Process (f) may also be carried out in conventional manner using either acid or basic conditions as described in the literature. By way of illustration reference is directed to the textbook Buehler and Pearson, ibid at pages 751-754.
Process (g) may also be carried out in conventional manner using ammonia or amine preferably in alcoholic solution. Again by way of illustration reference is drawn to the textbook Buehler and Pearson, ibid pps 899-902. Where an acid halide is used as starting material it is preferred to employ an acid salt thereof in order to minimise reaction of the starting material with itself.
The hydrolysis process (h) may be carried out under acidic or basic conditions in conventional manner eg.
ref fluxing in 10% alkali metal hydroxide followed by acidification.
Processes (i) and (j) may be conveniently carried out using conventional chemical oxidising agents, eg.
potassium dichromate, potassium permanganate and oxygen/platinum catalyst. These and other methods are given in standard textbooks, see for example Buehler and Pearson, ibid, pps 545-549 and 760-764. Where process (j) is used to provide an aldehyde, overoxidation to the acid can be avoided by selective oxidation methods as described on pages 546-8 of Buechler and Pearson.
With regard to process (k) oxidation of the compound of formula VII wherein D3 is COCH3 may be effected by treatment with halogen and alkali (ie. the well known haloform reaction) eg. by adding a solution of sodium hypochlorite or hypobromite to the ketone in alcoholic solvent. Oxidation of the compound of the formula VII wherein D3 is CH=CH2 or-C-=CH may be effected by using potassium permanganate, potassium iodate or ozone.
Hydrolysis process (l) is conveniently carried out under acidic conditions eg. ref fluxing in dilute sulphuric acid.
Esterification process (m) may be effected by conventional means involving reaction with an alcohol ROH, see for example Buehler and Pearson, ibid, pps 802-809. Conveniently the reaction of the acid may be carried out with the alcohol as solvent and in the presence of mineral acid (eg. HCl). The acid halide is conveniently in the form of an acid salt prior to reaction with the alcohol and the reaction is preferably carried out in base, eg. dimethylaniline or pyridine.
Process (n) may be carried out in the usual manner using a halogenating agent, eg. phosphorus trichloride or tribromide, phosphorous pentachloride or thionyl chloride.
Reduction process (o) may be carried out using a reducing agent which reduces acids to alcohols eg. a hydride such as borane.
The starting materials of formula II used in process (a) are known compounds or can be prepared by analogous methods eg. by reducing an amide of formula 1 1 Ar-A-NHCO-E where E has one CH2 group less than E.
Compounds of formula V can be prepared by acylating a corresponding compound of formula Ar-A-NH-B-D using an acid chloride of formula R4 COCl. Compounds of formula Ar-A-NH-B-D can themselves be prepared by alkylating amines of formula NH2-B-D using a halide of formula Ar-A-hal.
Compounds of formula VI can be prepared by acylating amines of formula Ar-A-NH-E using an acid chloride of formula C1CO.BI -D2 wherein the variables have the values defined in connection with process (d).
Compounds of formula VII may be prepared by a process analogous to process (a) above using a compound of formula II and compound of formula hal-B-D Compounds of formula VIII may be prepared by reacting a compound of formula IX:
T1 2 with a compound of formula T CH2T , eq a malonic acid ester in the presence of a base, eg. sodium hydride or sodium ethoxide. The compound of formula IX may itself be prepared by reaction of phosphorus tribromide and a compound of formula I wherein D is -CH2OH.
Starting materials for the processes described herein are known compounds or can be prepared by analogous methods for known compounds.
In any of the aforementioned reactions compounds of formula (and Ia) may be isolated in free base form or as acid addition salts as desired. Examples of such salts include salts with pharmaceutically acceptable acids such as hydrochloric, hydrobromic, hyroiodic, sulphuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, succinic, malonic, formic, maleic acid or organosulphonic acids such as methane sulphonic or tosylic acid.
When acidic substituents are present it is also possible to form salts with bases eg. alkali metal (such as sodium) or ammonium salts eg.
trimethylammonium. Such salts of the compounds of formula I and Ia are included within the scope of this invention.
This invention also provides pharmaceutical compositions comprising a compound of formula Ia or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient.Suitable solid carriers are magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers, which is thus in association with it. Similarly cachets are included.
Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups, and elixirs.
The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such a sterile water, sterile organic solvent or a mixture of both.
The active ingredients can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. Other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. The composition may be administered orally, nasally, rectally or parenterally.
Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 1 to 500 mg or more, eg.
25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form. Based on the results from animal studies the dosage range for the treatment of humans using a compound of formula I will be in the range from about 1 mg to 2 g per day depending on the activity of the compound.
The following Examples illustrate the invention and methods for preparing compounds of the invention.
EXAMPLE 1 4-[N,N-Bis-(4-Chlorobenzyl)amino]butyronitrile Bis-C4-chlorobenzyl)amine hydrochloride [prepared by reducing N-(4-chlorobenzyl)-4-chlorobenzamide with lithium aluminium hydride in tetrahydrofuran] was basified using sodium carbonate in methylene dichloride solvent to give after rotary evaporation 3.16g of the free base as an oil. This was then mixed with 4-bromobutyronitrile (1.19ml), diisopropylethylamine (2.lml) and 25 ml of dry dimethylformamide and the mixture stirred at 80"C under nitrogen for 24 hours.
On cooling water (100cm3) was added and then the mixture was extracted with 1 x 50ml and 2 x 25ml of methylene dichloride. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil. This was further purified by column chromatography (silica column eluted with toluene) to give 2.83g of the title product as an oil.
2.8g of the title compound was dissolved in 10 ml hot ethanol, acidified with 0.76g (1 equiv,) of oxalic acid, diluted with ether and cooled to give, after filtration, the l:?-ethanedioate salt (1.78g) as colourless crystals, mp 124-6" (dec).
Analysis C18H18Cl2N2 . C2H2O4 requires C,56.8; H,4.8; N,6.6 Found: C, 57.0; H, 4.9; N,6.2%.
EXAMPLE 2 4-[N,N-Bis-(4-Chlorobenzyl)amino]butyric acid 1.36g of 4-[N,N-bis-(4-chlorobenzyl)amino]butyronitrile (as-produced in Example 1), water (25ml) and concentrated hydrochloric acid (10ml) were stirred and heated to reflux for 54 hours under a nitrogen blanket.
After cooling,an oil was obtained which crystallised on scratching. The crystals were filtered, washed with dilute hydrochloric acid, then with diethyl ether and recrystallised from isopropanol ether. Filtration and drying at 60 /1mm Hg gave the title compound as the hydrochloride salt (0.32g) m.p. 206-208 C(dec) Analysis C18 H19 NO2. HCl requires C,55.6; H,5.2; N,3.6 Found: C,55.4; H,5.2; N,3.7%.
EXAMPLE 3 4-[N,N-Bis-(4-chlorobenzyl)amino]butyramide A solution of 4-[N,N-Bis-(4-chlorobenzyl)amino]butyronitrile (2.0g) prepared according to Example 1 in dichloromethane (10ml) was cooled in ice, then treated with the phase-transfer catalyst nBu4NHSO4 (0.5g), 20% aq NaOH (3.2ml) and 30% H202(4.Oml). The mixture was stirred vigorously at 0 for about half an hour, then at room temperature for 23 hours. After dilution with dichloromethane the layers were separated1 and the organic phase washed with water and with dil. aq.
NaHSO32 then dried (MgSO4). Filtration and evaporation gave a syrup (2.26g) which was flash-chromatographed on neutral alumina eluted with neat toluene (to remove starting material (0.3g)) and then with 10% EtOH-toluene to recover the product (1.62g). Repeat chromatography on silica eluted with 2-5% EtOH-toluene gave the title compound (1.55g; 73.6%) as a syrup which set solid on standing. The resulting crystals had m.p.
66-76 .
Analysis C18 H20 N2OCl2 requires: C, 61.6; H, 6.0; N, 8.0 Found: C, 61.5; H, 5.8; N, 8.0%.
EXAMPLE 4 4-(N,N-Dibenzylamino)butyramide a) By a method analogous to Example 1 dibenzylamine was reacted with 4-bromobutyronitrile to give 4-(N,N-dibenzylamino)butyronitrile, mp. 45-46"C.
b) Hydrogen peroxide (30% w/v; 5.6ml), tetra-n-butylammonium hydrogensulphate (1.70g) and SN aqueous sodium hydroxide (4ml) were added to a stirred solution of 4-(N,N-dibenzylamino)butyronitrile (2.64g) in dichloromethane (10ml) with water cooling. The mixture was stirred vigorously at room temperature for 17 hours and dichloromethane (100ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (10ml), dried (Na2SO4) and concentrated in vacuo to give a viscous oil (4.12g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene ---- > ethyl acetate and recrystallised from cyclohexane to give the title compound (1.86g, 66%), m.p. 76 - 77 C.
Analysis C18 H22 N2O requires: C, 76.55; H. 7.85, N, 9.9 Found: C, 76.45; H, 7.95; N, 9.8% EXAMPLE 5 4-(N,N-Dibenzylamino)butyric acid A solution of 4-(N,N-dibenzylamino)butyronitrile (2.64g) in concentrated hydrochloric acid (50ml) was ref fluxed for 3 hours. The solution was concentrated in vacuo to give a solid, which was recrystallised from acetic acid and water to give the title compound as the monohydrochloride monoacetic acid salt (1.84g), m.p.
138 -139 C.
Analysis C18 H21 NO2.HCl. C2H4O2 requires:C,63.25; H,6.9;N,3.7% Found: C, 63.6, H, 7.2; N, 3.9 EXAMPLE 6 4-[N,N-Bis(4-methylbenzyl)amino]butyronitrile A solution of 4-bromobutyronitrile (i4.80g) in dry dimethylformamide (100ml) was added dropwise over 15 minutes to a stirred solution of bis-(4-methylbenzyl)amine (22.53g) and N,N-diisopropylethylamine (35ml 26g) in dry dimethylformamide (100ml). The solution was heated (oil bath 115 C) under nitrogen for 4 hours. The solution was poured onto a mixture of water (400ml) and saturated aqueous sodium chloride (400ml) and the mixture was extracted with ether (2 x 200ml).The extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil (39.55g). The product was chromatographed on silica with eluant diisopropyl ether, and dried at 100 C at 0.1mmHg for 4 hours to give 4-[N,N-bis(4-methylbenzyl)amino]butyronitrile (26g, 89%), which was used in Example 7 without further characterisation.
EXAMPLE 7 4-[N,N-Bis-(4-methylbenzyl)amino]butyramide Hydrogen peroxide (30% w/v; 5.67ml), tetra-n-butylammonium hydrogensulphate (1.70g) and 5N aqueous sodium hydroxide (4ml) were added successively to a stirred solution of 4-(N,N-bis-(4-methylbenzyl)amino]butyronitrile (2.93g) in dichloromethane (10ml), with water cooling.
The mixture was stirred vigorously at room temperature for 16 hours then dichloromethane (100ml) was added.
The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (1x10ml), dried (Na2 SO4) and concentrated in vacuo to give a viscous oil (4.61g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene ---- > ethyl acetate and triturated with cyclohexane to give the title compound (1.77g), m.p. 85 -86 C Analysis (Found: C,77.25; H, 8.35; N, 9.25; C20H26N2o requires C, 77.4; H, 8.45; N, 9.0%.
EXAMPLE 8 4-[N,N-Bis-(4-methylbenzyl)aminolbutyric acid 4-(N,N-Bis-(4-methylbenzyl)amino]butyronitrile (2.93g) was suspended in concentrated hydrochloric acid (50ml) and the mixture was refluxed (oil bath 130 C) for 4 hours. The solution was concentrated in vacuo to give a foam (4.17g). The product was triturated with hot water and crystallised in ether at -78 C to give the title compound as the hydrochloride, three quarters hydrate (2.82g), m.p. 148 -151 C Analysis C20 H25 NO2.HCl.0.75H2O requires:C,66.45;H,7.65; N,3.9.
Found: C, 66.2; H, 7.2; N, 3.95%.
EXAMPLE 9 4-EN,N-Bis-(3,4-Dichlorobenzyl)amino]butyronitrile Using a procedure analogous to Example 6, Bis-(3,4-dichlorobenzyl)amine (2.71g, 8.09mM) was reacted with 4-bromobutyronitrile (0.81ml) to give the title compound as an oil 1.97g.
Ir (film) CN 2230cm EXAMPLE 10 4-[N,N-Bis-(3,4-dichlorobenzyl)amino]butyric acid A mixture of 4-[N,N-bis-(3,4-dichlorobenzyl)amino]butyronitrile (1.95g), NaOH (2.0g) and ethanol (25ml) was stirred and heated to reflux for 6 hours under a nitrogen blanket.
After cooling, the solvent was evaporated in vacuo to give a paste which was taken up in water (30ml), acidified with conc. HCl, stirred well and cooled in ice. The oil which had precipitated crystallised slowly. The crystals were filtered off, washed well with water, and recrystallised from dimethylformamide, diluted with a large volume of ether. The precipitated oil again crystallised slowly. The crystals were triturated with hot isopropanol, diluted with ether, collected by filtration and dried at 500/lmm to give the title compound as the hydrochloride salt. (1.20g), m.p. 227-231 (decomp).
Analysis C18 H17 NO2 Cl4. HCl requires: C, 47.2; H, 4.0; N, 3.1 Found: C, 47.2; H, 4.0; N, 3.2%.
EXAMPLE 11 4-tN,N-Bis-(4-methoxybenzyl)amino]butyronitrile A solution of 4-bromobutyronitrile (14.80g) in dry dimethylformamide (100ml) was added dropwise over 15 minutes to a stirred solution of bis-(4-methoxybenzyl)amine (25.73g) and N,N-diisopropylethylamine (35ml, 26g) in dry dimethylformamide (100ml). The yellow solution was heated under nitrogen at 110 C for 4 hours and was allowed to cool. The solution was poured onto a mixture of water (400ml) and saturated aqueous sodium chloride (400ml) and then extracted with ether (2x200ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give an oil (35.93g).The product was chromatographed on silica with eluant diisopropyl ether, and was triturated with cyclohexane to give the title compound (26.00g), m.p. 56 -58 C.
Analysis C20H24N202 requires:C, 74.05; H, 7.45; N, 8.65.
Found: C, 73.85, H 7.4; N, 8.85%.
EXAMPLE 12 4-(N,N-Bis-(4-Methoxybenzyl)amino]butyramide Hydrogen peroxide (30% w/v; 5.67ml), tetra-n-butylammonium hydrogensulphate (1.70g) and 5N aqueous sodium hydroxide (4ml) were added successively to a stirred solution of 4-[N,N-bis-(4-methoxybenzyl)amino]butyronitrile (3.24g) in dichloromethane (10ml), with water cooling. The mixture was stirred vigorously at room temperature for 18 hours and dichloromethane (100ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (1x1Oml), dried (Na2 SO4) and concentrated in vacuo to give an oil (4.71g).The product was chromatographed on silica with eluant 20% ethyl acetate/toluene ---- > ethyl acetate, and crystallised from diisopropyl ether at room temperature to give the title compound (2.21g), m.p. 53-54 C.
Analysis: C20H26N203 requires :C, 70.15; H, 7.65; N, 8.2%.
Found: C, 70.0; H, 7.75; N, 8.15%.
EXAMPLE 13 5-(N,N-Dibenzylamino)pentanonitrile A solution of 5-bromopentanonitrile (16.20g) in dry dimethylformamide (100ml) was added dropwise over 15 minutes to a stirred solution of dibenzylamine (19.73g) and N,N-diisopropylethylamine (35ml, 26g) in dry dimethylformamide (100ml). The solution was heated (oil bath ii00C) for 4 hours and was allowed to cool.
The solution was poured onto a mixture of saturated aqueous sodium chloride (400ml) and water (400ml) and the mixture was extracted with ether (2 x 200ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give a mobile oil (30.32g).
The oil was chromatographed on silica with eluant diethyl ether to give the title compound (23.17g) as an oil which was used without further purification in Example 14.
EXAMPLE 14 5-(N,N-Dibenzylamino)pentanoic acid A solution of 5-(N,N-dibenzylamino)pentanonitrile (2.75g) in concentrated hydrochloric acid (50ml) was ref fluxed (oil bath 140"C) for 4 hours. The solution was allowed to cool, and the product crystallised. The mixture was concentrated in vacuo to give a white solid which was recrystallised from water, filtering out insoluble material, to give the title compound (2.96g), m.p. 202"-205"C.
Analysis C19H23NO 2.HCl requires:C, 68.35; H, 7.25; N, 4.2.
Found C, 68.15; H, 7.35; N, 4.2%.
EXAMPLE 15 4-N,N-(Bis-[2-(4-chlorophenyl)ethylaamino)butyronitrile In a manner analogous to Example 6, 5.08g of bis-[ 2-(4-chlorophenyl)ethyl ]amine was reacted with 1.73ml 4-bromobutyronitrile to give the title compound (5.83g).
EXAMPLE 16 4-N,N-(Bis-[2-(4-chlorophenyl)ethyl]amino)butyric acid A solution of the 4-(bis-[2-(4-chlorophenyl)ethyl3amino)butyronitrile (5.8g) and NaOH (5.7g) in ethanol (75ml) was stirred and heated to reflux for 6 hours and, after cooling, the solvent was evaporated and the residue was taken up in water, acidified with conc. HCl and the turbid mixture maintained at 5 C overnight, during which time an oil precipitated and solidified. The solid was collected by filtration and washed with water. It was then boiled for 1 hour with conc. HBr, cooled, kept at 5 until resolidification had occurred, and the solid was collected by filtration.Recrystallisation was twice effected by dissolution of the solid in hot isopropanol containing a few drops of water, followed by dilution with ether, to give crystals of the title compound as the hydrobromide salt, (4.03g), m.p. 150-2 (dec.; "sweating" occurs above 147 ).
Analysis: C20H23NO2Cl2.HBr requires: C,52.i;H,5.2;N,3.0 Found: C,52.2;H,5.4;N,3.25% EXAMPLE 17 Ethyl 4-[N,N-bis-(4-chlorobenzyl)amino]butanoate a) An ice-cooled, stirred suspension of 4-[N,N-bis-(4-chlorobenzyl)amino]butyric acid, hydrochloride salt (2.05g) prepared according to Example 2) in absolute ethanol (100ml) was treated with HCl gas for l hour. The solution was warmed to room temperature and allowed to stand overnight. The solvent was evaporated in vacuo, and the oily residue taken up in aqueous NaHCO3 and extracted with dichloromethane (2 x 25ml).The combined extracts were washed with water and dried CMgSO4). Filtration and evaporation gave an oil (1.86g) which was freed from residual acid by passage through a silica column, eluted with ethyl acetate. Evaporation of the eluate gave an oil (1.32g) which was dissolved in ethanol (5ml) and treated with oxalic acid t0.30g; 1 equiv.).
Evaporation of the solvent and treatment of the residue with hot ethyl acetate caused crystallisation to occur.
The crystals were collected by filtration and recrystallised from ethanol-ethyl acetate to give the title compound as the 1:1 ethanedioate salt (0.53g) as colourless crystals, m.p. 123.5-125 .
Analysis C20H23NO2Cl2.C2H204 requires:C,56.2;H,5.4;N,3.0 Found: C,56.3;H,5.5gN,2.7% b) The product of step (a) is converted to 4-[N,N-bis-(4-chlorobenzyl)amino] butyramide by treatment with ammmonium hydroxide.
EXAMPLE 18 4-[N,N-Bis-(4-Chlorobenzyl)amino)butanol A stirred suspension of 4-[N,N-bis-(4-chlorobenzyl)amino]butyric acid, hydrochloride (prepared according to Example 2) (13.44g) in dry tetrahydrofuran (250ml) was stirred and heated to reflux as borane-methyl sulphide (10 molar; 17ml; 5 equiv.) was added dropwise. The mixture was stirred and heated to reflux under a nitrogen blanket for 17 hours. After cooling, the mixture was decomposed by the dropwise addition of 10% aq H2SO4.
The organic solvent was evaporated in vacuo and the aqueous residue was diluted with 10% aq H2SO4(120ml) and heated to reflux for 3 hours.
The cooled solution was poured onto aqueous Na2CO3 and brine and extracted with dichloromethane (2 x 100ml).
The combined extracts, which showed a tendency to emulsify in the presence of water, were washed with brine and dried (MgSO4). Filtration and evaporation gave a viscous syrup (11.38g) which was purified by passage through silica gel, eluted with neat toluene and then with 2-5% ethanol/toluene to give an oil (9.40g).
A solution of the oil (7.50g) in hot ethanol (25ml) was treated with 2.58g (1 equiv) of fumaric acid. The crystals which separated overnight were triturated with boiling iso-propanol, cooled and refiltered, to give crystals of the title compound as the 1- fumaric acid salt (3.70g) mp. 141-143C (dec).
Analysis C18H21NOCl2.1-21 C4H404 requires:C,56.3;H,5.3;N,2.7 Found: C, 56.0; H,5.4; N, 2.6% EXAMPLE 19 (a) 4-[(N,N-(1,1-diphenyl)methyl-N-benzyl)amino]butyronitrile A solution of 4-bromobutyronitrile (7.40g) in dry dimethylformamide (50ml) was added dropwise over 5 minutes to a stirred solution of N-benzyl-1,1- diphenylmethylamine (13.67g)(prepared by reductive amination of benzophenone and benzylamine using sodium cyanoborohydride) and N,N-diisopropylethylamine (18ml, 13g) in dry dimethylformamide (50ml). The solution was heated at 1200C under nitrogen for 42 hours and was poured onto a mixture of saturated aqueous sodium chloride (200ml) and water (200ml). The mixture was extracted with ether (2 x 100ml) and the extracts were dried (Na2S04) and concentrated in vacuo to give an oil (21.27g). The product was chromatographed on silica with eluant dichloromethane. Fractions containing the desired material were evaporated to dryness at reduced pressure and dried at 110 C at 0.immHg for 4 hours to give 4-[(N-(1,1-diphenyl)methyl-N-benzyl)amino]butyronitrile as an oil (14.61g).
(b) 4-[(N,N-(1,1-Diphenyl)methyl-N-benzyl)amino]butyric acid A solution of the product of step (a) (3.40g) in absolute ethanol (100ml) was treated with sodium hydroxide pellets (20.0g). The mixture was ref fluxed for 4 hours and was concentrated in vacuo to give a solid. Water (200ml) and ice (200ml) were added and the mixture was acidified with concentrated hydrochloric acid (100ml) at 0 C. The mixture was concentrated in vacuo and the residue was triturated with isopropanol. The mixture was filtered and the solution was reconcentrated to give a foam (4.51g).
The product was dissolved in hot water and the mixture was filtered through kieselguhr. The filtrate was concentrated in vacuo to give a solid (2.21g), which was triturated with ethyl acetate, to give the title compound as the hydrochloride three quarters hydrate (1.90g.), m.p. 166 -173 C.
Analysis C24H25NO2.HCl.O.75H2O requires C, 70.4; H, 6.75; N, 3.4.
Found: C,70.65; H, 6.8; N, 3.05%.
EXAMPLE 20 a) 4-[N,N-Bis-(3-bromobenzyl)amino]butyronitrile A mixture of N,N-bis-(3-bromobenzyl)amine (13.47g; 0.038mol), 4-bromobutyronitrile (3.77ml; 0.038mol), diisopropylethylamine (10ml; 0.057mol), potassium iodide (1g) and dimethylformamide (30ml) was stirred under a nitrogen blanket at 80-90 for 22 hours. After cooling, the solvent was evaporated and the residue was taken up in aq. Na2CO3 and extracted with dichloromethane. The combined extracts were washed with aq. Na2CO3 and dried (MgSO4). Filtration and evaporation gave an oil (18.49g), which was chromatographed on silica eluted with 1% v/v ethanol-toluene. Evaporation of fractions containing product gave the title compound (12.36g; 77.2%) as an oil.A solution of the product (0.84g; 2mmol) in hot ethanol (5ml) was treated with oxalic acid (0.18g; 2mmol) Crystallisation occurred overnight and the crystals were collected by filtration and recrystallised from ethanol-ether to give the 1:1 ethanedioate salt (0.22g), mp. 120-122 C.
Analysis C18H18Br2N2.(COOH)2 requires: C, 46.9; H, 3.9; N, 5.5.
Found: C,47.1; H,4.1; N, 5.3%.
b) 4-[N,N-Bis-(3-bromobenzyl)amino]butyric acid A solution of 4-[N,N-bis-(3-bromobenzyl)amino]butyronitrile (12g) and ethanol (120ml) was stirred and heated to reflux for 17.5 hours under nitrogen. After cooling, the solvent was evaporated in vacuo. The residue was taken up in water (120ml) and strongly acidified with conc. HCl (36ml). The mixture was cooled in ice, causing an oil to precipitate. The oil crystallised after standing overnight and was filtered off and triturated with hot isopropanol. After cooling, the crystals were collected by filtration and washed with ether to give crystals of the title compound as the hydrochloride salt (10.87g), mp.
156-159"C.
Analysis C18 H19Br2 NO2. HCl requires: C,45.3, H,4.2; N,2.9 Found: C,45.0; H,4.5; N, 2.5% EXAMPLE 21 a) 4-[N,N-Bis-(3-chlorobenzyl)amino]butyronitrile A mixture of bis-(3-chlorobenzyl)amine (8.0g; 0.03 mol), potassium iodide (5.0g; 0.03 mol), diisopropylethylamine (7.0 ml; 0.04 mol), 4-bromobutyronitrile (3.0 ml; 0.03 mol) and dimethylformamide (25 ml) was stirred and heated to an oil-bath temperature of 80"C for 18 hours, under a nitrogen blanket. After cooling, the solvent was evaporated and the residue taken up in dilute aqueous Na2CO3 and extracted with dichloromethane (3x50ml). The combined extracts were washed with water and dried (MgSO4). Filtration and evaporation gave an oil (11.0g) which was chromatographed on silica eluted with neat toluene and then with 2% v/v ethanol-toluene.The fractions containing product were collected and evaporated to give the title compound as an oil (8.59g).
A portion (i.iq) of the oil was converted to the 1:1 ethanedioate salt by addition of oxalic acid (one equivalent) in isopropanol. After evaporation of the solvent, the 1.1 ethanedioate salt of the title compound was obtained by crystallisation from ethyl acetate, m.p. 74-9 C.
Analysis C18H18Cl2N2. (COOH)2 requires: C,56.7; H,4.8; N,6.6 Found: C,56.3; H,4.6; N, 6.7% b) 4-[N,N-Bis-(3-chlorobenzyl)amino]butyric acid A solution of 4-[N,N-bis-(3-chlorobenzyl)amino]butyronitrile (8.59g; 0.026 mol), NaOH (10g; 0.25 mol) and ethanol (125 ml) was stirred and heated to reflux for 18 hours. After cooling the solvent was evaporated in vacuo and the solid residue taken up in water (75 ml). After further cooling in ice, conc. HCl was added until the mixture was strongly acid (ca. 25 ml required). The initially precipitated oil hardened to a solid, which was collected by filtration and recrystallised from dimethylformamide-ether and then from 10% v/v water-isopropanol followed by dilution with ether.After drying at 45"C/lmm the hydrochloride hemihydrate salt of the title compound was obtained (5.60g). m.p. 170-173 (dec.; softens above 166 ).
Analysis C18H19Cl2NO2. HCl. tH20 requires: C,54.4; H,5.3; N,3.5 Found C, 54.4; H,5.2; N,3.5%.
EXAMPLE 22 4-[N,N-Bis-(2-thienylmethyl)aminoabutyric acid a) In a manner analogous to Example 21a, 4-[N,N-bis-(2-thienylmethyl)amino]butyronitrile was prepared by alkylation of bis-(2-thienylmethyl)amine usig 4-bromobutyronitrile.
b) In a manner analogous to Example 2 4-[N,N-bis (2-thienylmethyl)amino]butyronitrile (12g) was hydrolysed using concentrated hydrochloric acid (200 ml) to give the title compound as an oily-solid residue. Isopropanol (150ml) was added and the mixture cooled with stirring. Precipitated NH4Cl was removed by filtration and the filtrate was concentrated and filtered to remove further inorganic material. The filtrate was partitioned between aqueous NaOH and toluene. After standing overnight, the layers were separated, the aqueous phase was acidified to pH1, concentrated in vacuo, diluted with isopropanol, filtered to remove precipitated NaCl, and evaporated to dryness to give a solid.
The solid was chromatographed on silica eluted with 2% v/v ethanol-toluene, then with 10%- and 20%- v/v ethanol-toluene. The product-bearing fractions were evaporated, dissolved in isopropanol, filtered to remove a little solid material, concentrated in vacuo and diluted with ether. The initially-precipitated gum crystallised after standing for 72 hours. The solid was collected by filtration, purified by trituration with boiling isopropanol, cooled and filtered to give crystals of the title compound1 as the hydrochloride salt mp 158-160 .
Analysis: C 14H17NO2S2 HCl requires C, 50.7; H, 5.5; N, 4.2% Found C,50.5; H,5.6; N,4.1% EXAMPLE 23 4-[(N-4-Methylphenylmethyl-N-phenylmethyl)amino]- butyric acid a) In a manner analogous to Example 21a, 4-[(N-4methylphenylmethyl-N-phenylmethyl)amino]butyronitrile was prepared by alkylation of N-C4-methylphenylmethyl)- benzenemethanamine (4.22g) using 4-bromobutyronitrile (2ml). Yield 4.45g.
b) In a manner analogous to Example 10 the nitrile from step (a) above was hydrolysed using NaOH in ethanol to give, after acidification with HBr, the title compound as the hydrobromide, quarterhydrate salt, mp 119-125 C.
Analysis C19H23NO2. HBr. w1H2O requires: C, 59.6; H,6.5; N, 3.7 Found: C, 59.5, H, 6.75; N, 3.5%.
EXAMPLE 24 4-[N,N-Dibenzyl]amino-N'N'-dimethylbutyramide A sample of 4-[N-N-dibenzyl]aminobutyric acid (8.51g, 0.03 moles) (prepared according to Example 5) was dissolved in dry acetonitrile (50ml) under nitrogen.
1,1 -Carbonyldiimidazole (4.85g) was dissolved in dry acetonitrile and added dropwise over 1 hour. The mixture was stirred under nitrogen for 96 hours. An excess of dimethylamine (10g. 0.22 moles) was added, and the mixture stirred for a further two hours.
Evaporation gave a residue which was separated on a silica column with ethyl acetate as eluant. Ten 50 ml fractions were collected; the product appearing in fractions 5-8. Evaporation gave an oil which was dissolved in ether. Acidification with ethereal HCl to pHl gave a precipitate which was recrystallised from ethyl acetate/isopropanol to give crystals of the title compound as the hydrochloride, quarterhydrate, mp.
166-171.
Analysis C20 H26 N20. HCl. -H20 requires C2 68.5; H,7.9; N,8.0.
Found C, 68.7; H, 8.0; N, 8.0% EXAMPLE 25 4-[N,N-Bis-(1-Naphthalenemethyl)amino]butyric acid a) 1-Naphthoyl chloride (5.0g, 0.026 moles) in CH2Cl2 (25ml) was added dropwise to a stirred solution of ice cooled l-naphthalenemethylamine in CH2Cl2 (25ml). A white precipitate formed immediately. The mixture was stirred at room temperature for 3 hours then filtered.
The precipitate was washed with water and hot ethanol, then dried to give N-(l-naphthalenylmethyl l-naphthaleneacetamide (5.18g, 0.017 moles).
The amide (5.18g) was dissolved in tetrahydrofuran (25ml) then added dropwise to LiAlH4(0.63g 0.016 moles) in tetrahydrofuran (25ml). The mixture was heated at reflux for 24 hours, then worked up by dropwise addition of water (0.6ml), 15% aq NaOH(0.6ml) and water (1.9ml). Filtration, drying (MgSO4) and evaporation gave an oil (22.5g) which was crystallised from ice-cold ethanol to give N,N-bis (1-naphthalenemethyl)amine (2.54g) (b) The amine from step (a) (2.54g) was dissolved in DMF (20ml), then 4-bromobutyronitrile (0.76 ml, 0.0076 moles) and diisopropylethylamine (4.07ml 0.023 moles) in DMF (25 ml) added dropwise. Potassium iodide (1g) was added and the mixture heated at reflux for 24 hours.Evaporation gave a solid which was taken up into Na2CO3 (50ml), extracted into CH2Cl2 (3x25ml) dried (MgSO4) and evaporated to give a solid.
Separation on a silica column with 10% v/v ethyl acetate in toluene as eluant, followed by evaporation, gave 4-[N,N-bis(1-naphthalenemethyl)amino]butyronitrile (1.54g).
(c) The nitrile from step (b) (1.54g) was dissolved in isopropanol (25ml), then NaOH (i.0g, 0.024 moles) was added and the mixture heated at reflux for 24 hours.
Evaporation gave a residue which was taken up into water and extracted with CH2Cl2 (3x30ml). Drying and evaporation gave a solid which was partially dissolved in ether, then precipitated with ethereal HCl.
Filtration, trituration with HCl followed by ice-cold water gave the title compound as the hydrochloride hemihydrate, (1.62g) m.p. 187-191 C.
Analysis C26 H25 NO2. HCl. 2H2O requires: C,72.8; H,6.4; N,3.3.
Found: C, 72.7; H,6.6; N, 3.5%.
EXAMPLE 26 4-[N-(p-Chlorobenzyl)-N-methylamino]butyramide A solution of 4-[N-(p-chlorobenzyl)-N-methylamino]butyronitrile (0.95g; 4.27mmol) in dichloromethane (5ml) was cooled in ice as nBu4NHSO4 (0.3g) was added, followed quickly by 20% w/v aq NaOH (1.6ml) and 30% hydrogen peroxide (2.oil). The mixture was stirred vigorously, briefly at 0 C and then at room temperature, for 2 hours. After dilution with more dichloromethane, the layers were separated, the organic phase was washed with water and dried (MgSO4).
Filtration and evaporation gave an oil (0.83g) which was chromatographed on silica eluted with toluene containing an increasing proportion of isopropanol (to 50% v/v). The product was obtained as an oil (0.52g) which set solid on standing, to give the title compound (0.52g) m.p. 62-64".
Analysis C12 H17 ClN2O requires: C, 59.9; H, 7.1; N, 11.6 Found: C, 60.0; H, 7.1; N, 11.9% EXAMPLE 27 4-[N-Methyl-N-(4-chlorobenzyl)amino]butyric acid A mixture of 4-[N-methyl-N-(4-chlorobenzyl)amino]butyronitrile (4.65g; 0.021 mol) and NaOH (5g; 0.125 mol) in ethanol (50ml) was stirred and heated to reflux under a nitrogen blanket for 21 hours. The solvent was evaporated to give a paste, which was dissolved in water (50ml) and strongly acidified with conc. HCl (ca.
12ml). The solvents were again evaporated, and the residual, semi-crystalline mass was boiled briefly with isopropanol, filtered, and the inorganic precipitate washed well with isopropanol. The filtrate was evaporated to give a syrup (7.47g) which was crystallised in several crops from isopropanol/ether.
The combined crops were triturated with boiling isopropanol, cooled, filtered and dried at 50"/lmm to give the title compound as the hydrochloride salt (4.22g) m.p. 149-152".
Analysis C12 H16 ClNO2. HCl requires C, 51.8; H, 6.2; N, 5.0 Found: C, 51.5; H, 6.2; N, 5.0% EXAMPLE 28 In a manner analogous to Examples 26 and 27, nitrides of formula X shown below were hydrolysed to the corresponding acids or partially hydrolysed to the amide as shown below:
in which formulae Ar, R and B represent: Ar R B 2-furanyl 2-furanyl -(CH2)3 2-furanyl hydrogen -(CH2)3 3-pyridyl 3-pyridyl -(CH2)3 3-quinolyl 3-quinolyl -(CH2)3 2-thiazolyl 2-thiazolyl -CCH2)3 -

Claims (21)

  1. CLAIMS A A compound characterised in that it acts selectively as an agonist of gamma aminobutyric acid (GABA) at GABA autoreceptors for use as an antidepressant or in treating senile dementia with the proviso that the compound is not fengabine or progabide.
  2. 2. Use of a compound which acts selectively as an agonist of GABA at GABA autoreceptors in the preparation of a medicament for the treatment of depression or senile dementia with the proviso that the compound is not fengabine or progabide.
  3. 3. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.
  4. 4. A compound, use or composition according to any one of Claims 1-3 in which the selectivity for the GABA autoreceptor relative to the GABAA receptor is greater than or equal to 100.
  5. 5. A compound1 use or composition according to any one of Claims 1-3 in which the selectivity for the GABA autoreceptor relative to the GABAA receptor is greater than or equal to 1000.
  6. 6. A compound, use or composition according to any one of Claims z to 5 wherein the GABA autoreceptor agonist is a trisubstituted amine in which one substituent is a 3- or 4- carbon alkyl group carrying a carboxylic acid or amide functional group.
  7. 7. A compound, use or composition according to any one of Claims 1 to 6 wherein the GABA autoreceptor agonist has the formula:
    wherein E is lower alkyl or Ar -A Ar and Ar are the same or different optionally substituted aryl groups; A and A are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar to N, each optionally substituted by lower alkyl or optionally substituted aryl; B is an alkylene group of 3 or 4 carbon atoms which may be substituted by lower alkyl; D represents COOH or CONR R wherein IR R and R are independently hydrogen, lower alkyl or aralkyl of 7 to 12 carbon atoms or a pharmaceutically acceptable salt thereof.
  8. 8. A compound of formula Ia as shown and defined in Claim 7 or a pharmaceutically acceptable salt thereof providing that neither Ar-A or E is unsubstituted benzyl.
  9. 9. A compound, use or composition according to Claim 7 or Claim 8 in which Ar and Ar when present are independently selected from mono- or bi-cyclic carbocyclic aryl groups of 6 to 10 carbon atoms and mono- or bi-cyclic heterocyclic aryl groups of 5 to !0 ring atoms in which the heteroatom(s) present is/are selected from nitrogen, oxygen and sulphur.
  10. 10. A compound, use or composition according to Claim 9 wherein Ar and Ar when present are selected from phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, quinolinyl and benzofuranyl which groups may be optionally substituted.
  11. 11. A compound, use or composition according to Claim '0 in which the optional substituent is selected from one or more of the following lower alkyl, lower alkoxy, halogen, haloloweralkyl, halolower alkoxy, nitro, cyano and optionally substituted amino.
  12. 12. A compound, use or composition according any one of Claims 7 to 1 1 wherein A and A when present are independently selected from -CHR -where R is hydrogen, lower alkyl or optionally substituted aryl as defined for Ar.
  13. '3. A compound, use or composition according to any one of Claims 7 to 12 wherein B is -CCH2 ) 3- or -CCH2 ) 4- or such a group substituted by methyl.
  14. 14. A compound, use or composition as claimed in any one of Claims 7 to 13 wherein R and/or R are/is hydrogen, methyl, ethyl, propyl or benzyl.
  15. '5. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-(4-chlorobenzyl)amino]butyric acid or a pharmaceutically acceptable salt thereof.
  16. '6. A compound1 use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-{N,N-bis-(4-chlorobenzyl)aminolbutyramide or a pharmaceutically acceptable salt thereof.
  17. 17. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-(4-methylbenzyl)amino]butyramide or a pharmaceutically acceptable salt thereof.
  18. '8. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-(3,4-dichlorobenzyl)aminolbutyric acid or a pharmaceutically acceptable salt thereof.
  19. 19. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-{N,N-bis-C3,4methoxybenzyl)amino1butyric acid or a pharmaceutically acceptable salt thereof.
  20. 20. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-CN,N-bis-[2-(4-chlorophenyl)ethyl]amino)butyric acid or a pharmaceutically acceptable salt thereof.
  21. 21. A compound of formula Ib whenever prepared by a process according to Claim 19 or Claim 20.
    21. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[(N-(,-diphenyl)methyl-N-benzyl)amino]butyric acid or a pharmaceutically acceptable salt thereof.
    22. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-(3-bromobenzyl)aminolbutanoic acid or a pharmaceutically acceptable salt thereof.
    23. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N;N-bis-(3-chlorobenzyl)aminoIbutanoic acid or a pharmaceutically acceptable salt thereof.
    24. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-(2-thienylmethyl)aminolbutanoic acid or a pharmaceutically acceptable salt thereof.
    25. A compound7 use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-t(N-4-methylphenylmethyl-N-phenylmethyl)aminol- butanoic acid or a pharmaceutically acceptable salt thereof.
    26. A compounds use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N,N-bis-C1-naphthalenemethyl)amino]butanoic acid or a pharmaceutically acceptable salt thereof.
    27. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N-Cp-chlorobenzyl)-N-methylamino]butyramide or a pharmaceutically acceptable salt thereof.
    28. A compound, use or composition according to Claim 7 or Claim 8 in which the compound of formula Ia is 4-[N-methyl-N-p-chlorobenzylamino]butanoic acid or a pharmaceutically acceptable salt thereof.
    29. A compound, use or composition according to Claim 7 in which the compound of formula Ia is 4-[N,N-dibenzylamino)butyric acid or a pharmaceutically acceptable salt thereof.
    30. A compound, use or composition according to Claim 7 in which the compound of formula Ia is 5-[N,N-dibenzylamino)pentanoic acid or a pharmaceutically acceptable salt thereof.
    31. A compound, use or composition according to Claim 7 in which the compound of formula Ia is 1 1 4-UN,N-dibenzyl]amino-N ,N -dimethylbutanamide or a pharmaceutically acceptable salt thereof.
    32. A compound according to anyone of claims 7 to 3! when in the form of a an acid addition salt from an acid selected from hydrochloric,sulphuric, phosphoric, hydrobromic, nitric, acetic, hydroiodic, citric, tartaric, fumaric, succinic, malonic, formic, maleic, methanesulphonic and p-tolysulphonic acid.
    33. A compound of formula I
    or a salt thereof, wherein Ar, A, E, and B are as defined in any one of Claims 7-'3 and D is D as defined in Claim 7 or Claim 54 or D is CN, COhal, CH2OH, CHO or an ester function COOR providing that (i) neither Ar-A- or E is unsubsitututed benzyl and (ii) when B is -CCH2)4 - and D is CN then E is other than methyl, ethyl or p-chlorobenzyl 34.A process for preparing a compound of formula I as defined in Claim 33 which comprises one of the following processes: a) reacting a compound of formula II Ar-A-NH-E (II) wherein Ar, E and A are as defined above with a compound of formula III: hal-B-CN r III) wherein B is as defined above and hal represents chlorine or bromine, to give a compound of formula I wherein D is CN, or b) carrying out a reductive alkylation of a compound of formula II as defined above using a compound of formula IV
    wherein B is an alkylene chain of 2 or 3 carbon atoms optionally substituted by lower alkyl, in the presence of a reducing agent such as sodium cyanoborohydride to give a corresponding compound of formula I wherein D is CN and B represents -CH2-B -; or (c) reducing a compound of formula (V)
    wherein R4 is alkyl of 1 to 5 carbon atoms or Ar-A-; Ar, Ar , A and B are as defined above, 3 2 D represents CN, COOR or COOH and A represents a direct bond or alkylene of 1 carbon atom optionally substituted by lower alkyl and/or aryl to give a corresponding compound of formula I wherein D is CN, 4 4.
    COOR or COOH and E is IR CH2 wherein IR is as defined above; or (d) reducing a compound of formula (VI)
    1.
    wherein Ar, A and E are as defined above, B is as defined in connection with formula IV and D2 represents CN, COOR or CHO to give a corresponding compound of formula I wherein B is -CH2B- and D is CN, COOR or CHO, or (e) partially hydrolysing a compound of formula I wherein D is CN to give a corresponding compound of forumla I wherein D is CONH2; or (f) hydrolysing a compound of formula I wherein D is CN or CONH2 to give a corresponding compound of formula I wherein D is COOH; or (g) reacting a compound of formula I wherein D is COOR or COhal with ammonia or an amine of formula HNIR IR to give a corresponding compound of formula I 12 wherein D is -CONR IR or (h) hydrolysing an ester of formula I wherein D is COOR to give a carboxylic acid of formula I wherein D is COOH; or (i? oxidising an aldehyde of formula I wherein D is CHO to give an acid of formula I wherein D is COOH; or (j) oxidising an alcohol of formula I wherein D is -CH2OH to give an aldehyde or an acid of formula I wherein D is CHO or COOH; or (k) oxidising a compound of formula
    wherein Ar, A, E and B are as defined above and D3 is COCH3 or CH=CH2 to give a compound of formula I wherein D is COOH; or (l) hydrolysing a compound of formula
    2 wherein Ar, A and E are as defined above,T' and T are each independently an ester function, a nitrile or an 1 acyl group, and B is an alkylene group of 2 or 3 carbon atoms optionally substituted by lower alkyl to give a corresponding compound of formula I wherein B is -B -CH2 - and D is COOH; or (m) esterifying an acid or acid halide of formula I wherein D is -COOH or COhal to give an ester of formula I wherein D is-COOR; or (n) halogenating an acid of formula I to give an acid halide of formula I wherein D is COhal; or (o) reducing an acid of formula I wherein D is COOH to give an alcohol of formula I wherein D is CH2OH, or (p) acidifying a compound of formula I to give an acid addition salt thereof or neutralising an acid addition salt to give the free base form.
    35. A process for preparing a compound of formula I substantially as hereinbefore described and illustrated in any one of Examples 1-3, 6-'2, '5-'8, 20a, 20b, 2'a, 21b, 22a, 22b and 25-27.
    36. A compound of formula I whenever prepared by a process according to Claim 34 or Claim 35.
    AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS 1. A compound of formula Ib
    or a salt thereof, 11 wherein E is lower alkyl or Arl-Al; Ar and Arl are the same or different optionally substituted aryl groups; A and Al are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar to N, each optionally substituted by lower alkyl or optionally substituted aryl; B is an alkylene group of 3 or 4 carbon atoms which may be substituted by lower alkyl; D represents CN, COhal, CH2OH, CHO or an ester function COOR providing that (i) neither Ar-A or E is unsubstituted benzyl, and (ii) when B is -(CH2)4- and D is CN then E is other than methyl, ethyl or p-chlorobenzyl.
    2. A compound according to Claim 1 in which Ar and Ar when present are independently selected from mono- or bi-cyclic carbocyclic aryl groups of 6 to 10 carbon atoms and mono- or bi-cyclic heterocyclic aryl groups of 5 to 10 ring atoms in which the heteroatom(s) present is/are selected from nitrogen, oxygen and sulphur.
    3. A compound according to Claim 2 wherein Ar and Ar when present are selected from phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, quinolinyl and benzofuranyl which groups may be optionally substituted.
    4. A compound according to Claim 3 in which the optional substituent is selected from one or more of the following lower alkyl, lower alkoxy, halogen, haloloweralkyl, halolower alkoxy, nitro, cyano and optionally substituted amino.
    5. A compound according any one of Claims 1 to 4 wherein A and Al when present are independently selected from -CHR3-where R3 is hydrogen, lower alkyl or optionally substituted aryl as defined for Ar.
    6. A compound according to any one of Claims 1 to 5 wherein B is -(CR2)3- or -(CH2)4-or such a group substituted by methyl.
    7. 4-[N,N-bís-(4-chlorobenzyl)amino]butyronitrile or a salt thereof.
    8. 4-[N,N-bis-(4-methylbenzyl)amino]butyronitrile or a salt thereof.
    9. 4-[N,N-bis-(3,4-dichlorobenzyl)amino]butyronitrile or a salt thereof.
    10. 4-[N,N-bis-(3,4-methoxybenzyl)amino]butyronitrile or a salt thereof.
    11. 4-(N,N-bis-[2-(4-chlorophenyl)ethyl]amino)- butyronitrile or a salt thereof.
    12. Ethyl 4-[N,N-bis-(4-chlorobenzyl)aminobutanoate or a salt thereof.
    13. 4-[N,N-Bis-(4-chlorobenzyl)amino]butanol or a salt thereof.
    14. 4-[N,N-bis-(3-bromobenzyl)amino]butyronitrile or a salt thereof.
    15. 4-[N,N-bis-(3-chlorobenzyl)amino]butyronitrile or a salt thereof.
    16. 4-[N,N-bis-(2-thienylmethyl)amino]butyronitrile or a salt thereof.
    17. 4-[N,N-bis-(l-naphthalenemethyl)amino]butyronitrile or a salt thereof.
    18. A compound according to anyone of Claims 1 to 17 when in the form of an acid addition salt from an acid selected from hydrochloric,sulphuric, phosphoric, hydrobromic, nitric, acetic, hydroiodic, citric, tartaric, fumaric, succinic, malonic, formic, maleic, methanesulphonic and p-tolysulphonic acid.
    19. A process for preparing a compound of formula Ib as defined in Claim 1 which comprises one of the following processes: a) reacting a compound of formula II Ar-A-NH-E (II) wherein Ar, E and A are as defined above with a compound of formula III: hal-B-CN (III) wherein B is as defined above and hal represents chlorine or bromine, to give a compound of formula Ib wherein D is CN, or b) carrying out a reductive alkylation of a compound of formula II as defined above using a compound of formula IV OHC-B1-CN (IV) wherein B1 is an alkylene chain of 2 or 3 carbon atoms optionally substituted by lower alkyl, in the presence of a reducing agent to give a corresponding compound of formula Ib wherein D is CN and B represents -CH2-B -;; or (c) reducing a compound of formula (V)
    wherein R4 is alkyl of 1 to 5 carbon atoms or Ar-A-; Ar, Ar, A and B are as defined above, D3 2 represents CN or COOR and A represents a direct bond or alkylene of 1 carbon atom optionally substituted by lower alkyl and/or aryl to give a corresponding compound of formula Ib wherein D is CN or COOR and E is R4CH2 wherein R4 is as defined above; or (d) reducing a compound of formula (VI)
    wherein Ar, A and E are as defined above, B is as defined in connection with formula IV and D2 represents CN, COOR or CHO to give a corresponding compound of formula Ia wherein B is -CH2Bl- and D is CN, COOR or CHO, or (e) oxidising an alcohol of formula Ib wherein D is -CH2OH to give an aldehyde or an acid of formula Ib wherein D is CHO ; or (f) esterifying an acid or acid halide of formula Ib wherein D is -COOH or COhal to give an ester of formula I wherein D is-COOR; or (g) halogenating an acid of formula Ib to give an acid halide of formula Ib wherein D is COhal; or (h) reducing an acid of formula Ib wherein D is COOH to give an alcohol of formula Ib wherein D is CH2OH, or (i) acidifying a compound of formula Ib to give an acid addition salt thereof or neutralising an acid addition salt to give the free base form.
    20. A process for preparing a compound of formula Ib substantially as hereinbefore described and illustrated in any one of Examples la, 3, 4, 5, 7, 8, 9, 11, 12, 13 and 15.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3712924A (en) * 1965-06-08 1973-01-23 Boehringer Sohn Ingelheim Halo-substituted 2-amino-benzylamineamides and salts thereof
GB1493416A (en) * 1974-04-08 1977-11-30 Philips Nv Spasmolytics
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Publication number Priority date Publication date Assignee Title
US3712924A (en) * 1965-06-08 1973-01-23 Boehringer Sohn Ingelheim Halo-substituted 2-amino-benzylamineamides and salts thereof
GB1493416A (en) * 1974-04-08 1977-11-30 Philips Nv Spasmolytics
EP0099685A2 (en) * 1982-07-16 1984-02-01 The Upjohn Company (3-Pyridinyl)heteroalkanols and alkanoic acids and esters
EP0177078A1 (en) * 1984-09-12 1986-04-09 Duphar International Research B.V Spasmolytically active tertiary amine derivatives and method of preparing the same
EP0187122A2 (en) * 1985-01-03 1986-07-09 Ciba-Geigy Ag 1,3,4-Trisubstituted azacycloalkanes or azacycloalkenes
EP0289070A1 (en) * 1987-04-10 1988-11-02 Duphar International Research B.V Tertiary arylethyl amine derivatives having opiate-antagonistic activity

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